Each year billions of health care dollars are spent on medical devices that fail in clinical practice (e.g., intravascular and neonatal catheters, coronary artery and vascular stents and grafts, guidewires, extracorporeal membrane oxygenation circuits, heart valves, by-pass circuits, etc.). These device failures are due to the introduction of a foreign material into the body leading to a multitude of serious health risks and undesirable complications including thrombosis, inflammation, cell proliferation, infection, and tissue overgrowth on the surface of the implanted device. Over the last 50 years, much has been learned about these device failures and attempts have been made to prevent failures using (1) alternative systemic drug therapies, (2) surface modifications on the device, or (3) a combination of both approaches.
Despite efforts to improve the efficacy of body-contacting and implantable medical devices, the incompatibility of materials within human blood and tissue still causes serious complications in patients. Thus, systemic or regional drug therapies remain necessary (e.g., use of heparin for short-term anticoagulation applications). Most often, when these drugs are administered they produce a systemic response in the patient. Systemic responses can mask blood chemistry problems and lead to a greatly increased possibility of complications and morbidity. Research studies examining alternative mechanisms are ongoing, but there is not yet an FDA-approved alternative material that overcomes all the problems associated with body-material interactions and systemic drug therapies. As such, in clinical practice today, all implanted devices eventually fail.
To approach the aforementioned shortcomings, it is worth considering the structure and function of the ideal blood-contacting material. Preferably this material would simultaneously inhibit multiple pathways of device complication (i.e., thrombosis, inflammation, cell proliferation and migration, restenosis as well as infection) but without causing systemic side effects of its own. Such a material strategy requires not only the identification of suitable therapeutic agent(s) with appropriate biological half-lives, but the approach also requires the material's architecture to be fabricated and tailored specifically to the needs of the clinical application. Thus, the approach to an ideal body-contacting material requires a biomaterial that can be systematically and dramatically tailored for use in a wide variety of devices while promising the simultaneous reduction in complicating factors. Currently, no material substrates exist that can be modified in such diverse ways without significantly altering the chemical, physical, or cytotoxicity properties of the material and, in turn, rendering the material unsuitable for clinical use. A modular biomaterial that can simultaneously reduce or eliminate thrombosis, inflammation, cell proliferation, and infection, and also attenuate normal tissue growth upon exposure to physiological fluid, such as blood, is paramount to improve and advance the efficacy of medical devices.
Nitric oxide is a free radical that is produced naturally by the body in several ways. Among these processes, the release and function of NO in endothelial cells (EC) has been the most extensively studied. For example, the endothelial cells that line all blood vessel walls produce NO via nitric oxide synthase (NOS) by the oxidation of L-arginine. The continuous release of NO from the EC has been shown to contribute significantly to the exceptional thromboresistivity and vascular function of a healthy vessel. For thromboresistivity, NO released from the EC into the blood stream temporarily “anesthetizes” any platelets that come close to the surface, preventing platelet adhesion and activation. In addition, NO prevents the formation of thrombi at sites of vascular injury and thus favors the dissolution of clot.
At the same time, NO produced by the ECs also diffuses into the underlying smooth muscle cells and acts as a vasoregulatory molecule. Results of in vivo studies have demonstrated that NO inhibits neointimal hyperplasia and causes vasorelaxation of surrounding cells. Because of these findings, agents that release nitric oxide have already been suggested as a potential pharmacological strategy for reducing intimal hyperplasia following balloon angioplasty procedures. In addition, researchers have shown NO as an effector in wound healing mechanisms and as an important regulator of angiogenesis and revascularization. Furthermore NO has been implicated in the control of sepsis, the treatment of tumors, neurotransmission, bone growth, and reproduction.
Despite the known uses of NO, NO materials that can be used clinically to release therapeutic amounts of NO at levels required to prevent thrombosis, restenosis, inflammation, and infection have not been reported. A primary problem with current approaches to incorporating NO therapeutic agents into medical devices is that the materials provide inadequate NO loading dosages. As a result, the currently available materials limit the length of time for useful NO fluxes to only a few days in most systems. While this may be suitable for some limited short-term medical applications, it is not viable for most implanted and blood-contacting medical devices. While this may be suitable for some limited short-term medical applications, it is not viable for most implanted and fluid-, tissue-, or cell-contacting medical devices, such as blood-contacting medical devices.
A significant cause of this issue is the structure and type of compound substrate upon which the NO moiety is currently attached. These substrates are organic compounds that are chemically limited in their capacity for loading NO and their ability to be structurally modified. High degrees of modification in the organic substrates to attempt to increase the NO loading amounts often lead to major changes in the physical, chemical, and mechanical properties of the material and render the material unsuited for use in medical applications. Further, many of these organic substrates are prone to decomposition, especially under physiological conditions, which leads to significant cytotoxicity issues due to the leaching of the decomposition byproducts. Further modifications to eliminate these problems often result in other structural inadequacies that render them unsuitable for clinical applications. To overcome these fundamental limitations, NO materials are needed that (1) produce significantly high levels of NO for long periods of time and (2) allow systematic modification while maintaining the structural properties that make them suitable for clinical applications.
There is a great need for a truly biocompatible material that minimizes biofouling and other deleterious side effects and simultaneously increases the lifetime of the medical device in a safe and efficacious manner. The result of such a material would decrease healthcare costs, improve the quality of care for patients, and decrease the time physicians spend repeating procedures.
In addition, there is a need for effective methods for using the material to treat clinically relevant disorders which this disclosure encompasses. Finally, a need exists to develop the coating method that allows for applying the material in a range of thicknesses or as encapsulated particles to broaden the utility of the material as outlined in this disclosure.